Statins are believed to reduce serum LDL cholesterol levels by inhibition of 3-hydroxy-3-methylglutaryl CoenzymeA reductase (HMG-CoA Reductase). Several statins are known, including Atorvastatin, Cerivastatin, Fluvastatin, Lovastatin, Mevastatin, Pitavastatin, Pravavastatin, Rosuvastatin and Simvastatin.
Statins have been proposed for use in the treatment of coronary heart disease, myocardial infarction, stroke and peripheral artery disease and the statins appear to have favorable effect in the treatment of inflammation, dementia neoplastic conditions, nuclear cataracts and pulmonary hypertension.
Many statins exhibit low water solubility and are practically insoluble in water. This hinders their effective use.
Our co-pending international patent application PCT/GB03/03226 describes the formation of solid, porous beads comprising a three dimensional open-cell lattice of a water-soluble polymeric material. These are typically ‘templated’ materials formed by the removal of both water and a non-aqueous dispersed phase from a high internal phase emulsion (HIPE) which has a polymer dissolved in the aqueous phase. The beads are formed by dropping the HIPE emulsion into a low temperature fluid such as liquid nitrogen, then freeze-drying the particles formed to remove the bulk of the aqueous phase and the dispersed phase. This leaves behind the polymer in the form of a ‘skeletal’ structure. The beads dissolve rapidly in water and have the remarkable property that a water-insoluble component dispersed in the dispersed phase of the emulsion prior to freezing and drying can also be dispersed in water on solution of the polymer skeleton of the beads.
WO 2005/011636 discloses a non-emulsion based spray drying process for forming ‘solid amorphous dispersions’ of drugs in polymers. In this method a polymer and a low-solubility drug are dissolved in a solvent and spray-dried to form dispersions in which the drug is mostly present in an amorphous form rather than in a crystalline form.
Our co-pending applications GB 0501835 and GB 0613925 (filed 13 Jul. 2006) describe how materials which will form a nano-dispersion in water can be prepared, preferably by a spray-drying process. In the first of these applications the water insoluble materials is dissolved in the solvent-phase of an emulsion. In the second, the water-insoluble materials are dissolved in a mixed solvent system and co-exist in the same phase as a water-soluble structuring agent. In both cases the liquid is dried above ambient temperature (above 20 Celsius), such as by spray drying, to produce particles of the structuring agent, as a carrier, with the water-insoluble materials dispersed therein. When these particles are placed in water they dissolve, forming a nano-dispersion of the water-insoluble material with particles typically below 300 nm. This scale is similar to that of virus particles, and the water-insoluble material behaves as though it were in solution.
WO 2003/103640 (Elan Pharma International Ltd) discloses nanoparticulate forms of statins (particularly Lovastatin or Simvastatin). Particle sizes are disclosed from 2000 nm down to 50 nm. Methods for the production of these nanoparticles include grinding, milling, homogenisation, and precipitation methods.
In the present application the term ‘ambient temperature’ means 20 degrees Celsius and all percentages are percentages by weight unless otherwise specified.